Introduction 10/27/10 ROLE OF NOVEL BIOMARKERS IN DISEASE PREVENTION: CRP, CT CALCIUM, AND CYSTATIN C

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1 ROLE OF NOVEL BIOMARKERS IN DISEASE PREVENTION: CRP, CT CALCIUM, AND CYSTATIN C Michael G. Shlipak, MD, MPH Professor of Medicine, University of California, San Francisco Chief, Division of General Internal Medicine, San Francisco VA Medical Center October 27 th, 2010 Introduction Biomarker- new term to represent a measureable biological process Biomarkers most often are blood tests, but can be from DNA, imaging, ECGs, etc. Biomarkers have major scientific roles other than clinical practice. Many primarily used in epidemiology to understand etiology of disease onset and progression Hlatky, Circulation 2009 Useful diagnostic tests- change our clinical management by: Distinguishing the presence/absence or severity of disease Changing our perception of disease risk, with clinical implications Modifiable Risk Factors- information is useful, as provides targets for intervention to reduce disease risk 1

2 Non-Modifiable Risk Factors- information changes individual s likelihood of disease, but does not provide specific target for therapy. Value of prognostic biomarkers is controversialmany new tests have unclear action plans Question 1: Which of the following best describes your attitude toward new diagnostic tests? 1. I am usually excited to use new tests to detect disease or disease risk. 2. I actively learn about new tests because my patients or peers expect me to be knowledgeable. 3. I generally don t like learning about new tests because they rarely improve clinical care. 4. If a test was not part of my clinical training, then I probably won t order it. Outline Update on Key Biomarkers: C-Reactive Protein (CRP) Coronary calcification by CT and other subclinical CVD measures Cystatin C 2

3 Question 2: My practice regarding CRP is best described as: 1. I measure CRP routinely to help with CVD risk stratification. 2. I measure CRP occasionally for challenging decisions for CVD prevention. 3. CRP is often measured as part of a lipid panel, but I rarely use the information. 4. I never think about CRP. C-Reactive Protein (CRP) Blood test that captures systemic inflammation Probably not in disease pathway; triggered by IL-6 CRP is very stable and easy to measure in blood Measuring inflammation has never been standard screening test CRP as a Risk Factor Emerging Risk Factors Collaboration Meta- Analysis: 38 studies 160,309 individuals 1.31 M person-years 27,769 outcomes Koptoge S et al. Lancet,

4 CRP and Heart Disease Risk Koptoge S et al. Lancet 2009 RR for 3-fold higher CRP-Mortality Koptoge S et al. Lancet 2009 Is the CRP-CVD Association Strong Enough? Although CRP is an independent risk factor, it does not add much beyond Framingham Risk Equation Explained partly by CRP s correlation with other cardiovascular risk factors CRP s relative risks only about 2-fold; to improve Framingham Risk Estimates, new risk factor needs RR 3.5 Lloyd-Jones DM et al., Ann Intern Med

5 CRP for Risk Classification CVD risk is classified as: Low Medium High < > 20 risk equivalent risk factors 2 risk factors Can CRP help classify correctly? Some have advocated CRP testing to help separate persons with medium risk Ridker PM et al., NEJM 2002 and Ann Intern Med 2009 Adding CRP to Framingham Risk Assessment in Women 30 Multivariate Relative Risk for CVD CRP Level < 1.0 mg/l CRP Level mg/l CRP Level >3.0 mg/l 0%-1% 2%-4% 5%-9% 10% Lloyd-Jones DM et al., Ann Intern Med 2006 Should CRP Levels be Used to Identify Statin Candidates? JUPITER Trial Design: 17,802 adults without CAD Rosuvastatin 20mg vs placebo Inclusion criteria: LDL < 130 (average 108) CRP > 2 (average 4.2) Outcomes: CVD, death 5

6 JUPITER Rosuvastatin Decreases CVD Risk Ridker PM et al., NEJM 2008 Key Points on JUPITER Statin trial, not a CRP study Demonstrated that statins are beneficial even in low-risk adults with normal LDL Statins likely also beneficial for persons with CRP < 2.0 Therefore, no clear justification to measure CRP USPTS Summary on CRP CRP- the most rigorously studied of novel CVD biomarkers CRP may classify some medium risk persons as high risk, but unclear: the yield of CRP testing why not aggressively treat all med. risk? Current evidence does not support the routine use of CRP for risk stratification Helfand M et al., Ann Intern Med

7 Outline Update on Key Biomarkers: C-Reactive Protein (CRP) Coronary calcification by CT and other subclinical CVD measures Cystatin C Question 3: The use of CT scans for CAD should be used: 1. As an alternative to coronary angiography (cath) for low risk patients. 2. To identify patients with CAD. 3. To decide who to give statins to. 4. There are no compelling indications to measure CT calcification. Coronary Calcification: Introduction CT scans have ability to detect calcium deposits in coronary (and other) arteries Presence of calcification is an indication of atherosclerotic plaque Therefore, detectable calcification in coronary arteries is an indicator of subclinical cardiovascular disease 7

8 Subclinical Cardiovascular Disease Defined as procedures (often radiological imaging) that detect early cardiovascular disease before clinically apparent Not developed as screening tests, but rather to study the development of CVD processes The Role of Subclinical CVD Measures Used to isolate risk factors, such as diabetes, for specific pathological processes that lead to CVD Often used as clinical trial outcomes for Phase 2 studies All valid subclinical CVD measures are associated with clinical CVD events. Current Subclinical CVD Measures Coronary artery calcification (CT)- MI risk Left ventricular hypertrophy (echo, MRI)- heart failure Carotid wall thickness (IMT by u/s)- stroke Ankle brachial index (SBP ratio)-peripheral arterial disease Vascular Stiffness (pulse wave velocity)- central hypertension Processes overlap, so most subclinical CVD measures predict multiple CVD outcomes 8

9 CT Coronary Artery Calcification Score and CAD Events- the MESA Study Detrano R et al., NEJM 2008 CAC Score and CAD Events by Race Detrano R et al., NEJM 2008 The Pros and Cons of CT Screening (or other testing for subclinical CVD) Pros: Stronger risk associations than CRP or other blood tests Specific for the presence of atherosclerosis Could potentially be useful for medium risk individuals needing motivation (e.g. my brother-in-law) ABI is inexpensive, relatively 9

10 The Pros and Cons of CT Screening (or other testing for subclinical CVD) Cons: In older populations and those with diabetes or kidney disease- nearly universal Not reproducible enough for repeat testing Not directly modifiable Radiation exposure $$$ Conclusion on CT-Calcium Score (or other testing for subclinical CVD) USPTF: current evidence does not support routine use of CT Also, does not recommend routine use of ankle brachial index or carotid wall thickness Helfand M et al., Ann Intern Med 2009 My opinion: if patient brings you a report documenting coronary calcification (or LVH, ABI < 0.9), then consider them high risk Outline Update on Key Biomarkers: C-Reactive Protein (CRP) Coronary calcification by CT and other subclinical CVD measures Cystatin C 10

11 Question 4: Regarding cystatin C 1. I first heard of it when I read the syllabus. 2. I saw paper(s) about it but have not read them. 3. I know it s a kidney test, but I don t use it. 4. I have measured cystatin C. What is Cystatin C? Cystatin C is a blood test of kidney function. FDA approved as an alternate measure of kidney function. Marketed by several companies, and is rapidly becoming commercially available. Filtration Marker Principles Creatinine and cystatin C are filtration markers Filtration marker-refers to something measurable in the blood that gives indirect information about the glomerular filtration rate (GFR) Production and elimination Factors affecting creatinine production: Muscle, activity, diet, health status Factors we use to estimate creatinine production Age, sex, race, weight 11

12 Properties of Cystatin C Cystatin C produced in all nucleated cells Constant release into blood, perhaps via cell turnover Freely filtered at glomerulus No renal tubular secretion Cystatin C association with GFR relatively independent of age, sex, race and muscle mass How can we compare tests of Kidney Function? GFR the virtual Gold Standard Measured by clearance of injected tracer Rarely clinically available Never available for population based cohort studies Our strategy- use clinical outcomes associated with kidney disease If cystatin C is better predictor of death or CVD, then probably a better marker of kidney function Comparison with Measured GFR 20 years of studies show cystatin C has closer approximation to measured GFR than creatinine DharnidharkaVR et al. AJKD 2002 Nearly all studies were in patients with kidney disease No GFR studies in the general population 12

13 Cardiovascular Health Study (CHS) Design: NIH sponsored cohort Subjects: Population based elderly cohort from 4 US communities N = 4,444 Mean age: 75 years Cystatin C measured at (Yr 3) visit Mean follow up: 9 years Outcomes: - All cause mortality - Cardiovascular mortality - Heart failure Creatinine Quintiles and Mortality Risk Mortality rate per year (%) Significant adjusted hazard ratio egfr<60 Creatinine 1st 2nd 3rd 4th 5th Quintiles Shlipak MG et al. N Engl J Med 2005 Cystatin C Quintiles and Mortality Risk Mortality rate per year (%) Significant adjusted hazard ratio 1st 2nd 3rd 4th 5th Quintiles Creatinine Cystatin-C Shlipak MG et al. N Engl J Med

14 Creatinine and Cardiovascular Mortality 5 4 Significant adjusted hazard ratio Mortality rate per year (%) 3 2 Creatinine 1 0 1st 2nd 3rd 4th 5th Quintiles Shlipak MG et al. N Engl J Med 2005 Cystatin C and Cardiovascular Mortality 5 Significant adjusted hazard ratio 4 Mortality rate per year (%) Creatinine Cystatin-C 0 1st 2nd 3rd 4th 5th Quintiles Shlipak MG et al. N Engl J Med 2005 Kidney Function and Heart Failure Incidence Incidence Rates per Year(%) Significant adjusted hazard ratio Cystatin C egfr Quintiles Sarnak MJ et al. Ann Intern Med

15 Confirmation Studies Cohort/Study Population Outcome(s) Health ABC Shlipak et al., JASN 2006 Bibbins-Domingo, Arch Intern Med 2006 Heart and Soul Ix, Circulation 2007 NHANES III Astor, JASN 2009 MDRD Study Menon, Arch Intern Med 2007 Elderly CAD General population Advanced CKD Death, heart failure Recurrent CVD Death Death What Clinical Need could Cystatin C Fill? Predicting risk- probably inadequate to justify ordering a new test (see CRP) However, 10s of millions of creatinine tests ordered each year Potential roles for cystatin C: Better classification of CKD Identifying preclinical impairment of kidney function Targeting specific populations with unpredictable muscle mass Pre-op risk stratification before surgery or contrast CKD Definition by Creatinine and Cystatin C In early work, we considered creatinine insensitive, but specific. However, from the nephrologist standpoint, specificity is a problem. Among 16 million in the U.S. with egfrcreat <60, who has real CKD? We compared prognostic value of CKD defined by creatinine and/or cystatin C Peralta CA et al., J Am Soc Nephrol, in press

16 CKD Definitions in the Elderly Cardiovascular Health Study- mean age 72 Rate (1000 person years) Rate of Mortality in CHS N=73% N=6% N=9% N=12% Neither Cystatin C Creatinine Both No CKD: 8% with missed CKD CKD definition CKD: 57% with real CKD CHS: CKD and Mortality All Cause Mortality Multivariate Adjusted Hazard Ratios with 95% Confidence Intervals 3345 deaths No Decreased egfr 1.00 (ref) Decreased egfrcr only 1.09 (0.98, 1.21) Decreased egfrcys only 1.78 (1.53, 2.08) Decreased egfr both 1.74 (1.58, 1.93) CHS: CKD and Cardiovascular Disease Cardiovascular Disease Multivariate Adjusted Hazard Ratios with 95% Confidence Intervals 2249 events No Decreased egfr 1.00 (ref) Decreased egfrcr only 1.05 (0.92, 1.20) Decreased egfrcys only 1.52 (1.26, 1.84) Decreased egfr both 1.46 (1.29, 1.65) 16

17 CHS: CKD and Heart Failure Heart Failure Multivariate Adjusted Hazard Ratios with 95% Confidence Intervals 1407 events No Decreased egfr 1.00 (ref) Decreased egfrcr only 0.99 (0.84, 1.18) Decreased egfrcys only 1.69 (1.33, 2.13) Decreased egfr both 1.43 (1.22, 1.67) CHS: CKD and ESRD Kidney Failure Multivariate Adjusted Hazard Ratios with 95% Confidence Intervals 84 events No Decreased egfr 1.00 (ref) Decreased egfrcr only 2.60 (1.00, 6.75) Decreased egfrcys only 6.14 (2.18, 17.29) Decreased egfr both (12.68, 44.76) CKD Definitions in the Middle-Aged Multi-Ethnic Study of Atherosclerosis- mean age ~60 Rate of Mortality in MESA CKD: 30% with real CKD Rate (1000 person years) N=88% N=2% N=7% N=3% Neither Cystatin C Creatinine Both No CKD: 2% with missed CKD CKD definition 17

18 Summary on CKD Classification A large proportion of CKD defined by creatinine are either false positives or low risk CKD. Cystatin C distinguishes the high risk CKD and identifies additional CKD missed by creatinine Practical Issues for Cystatin C Upcoming CKD Guidelines will discuss the clinical role of cystatin C Currently, limited availability of cystatin C because earlier method requires special machine At UCSF, has been available as a send out test New cystatin C assays -can be run on nearly all clinical chemistry analyzes. Costs: Medicare reimbursement: $19 Assay costs: $6/test Lab charges: variable Thank You Questions? 18